Humanizing bile acid metabolism in mice

Bile acids (BAs) play important roles in control of lipid, glucose and energy homeostasis. However, rodent-specific muricholic acids (MCAs) exert entirely different actions on BA receptors compared to the BA species present in humans. To allow evaluation of the interconnections between BAs and human diseases, we have generated mice with a human-like BA composition by deletion of Cyp2c70, responsible for rodent-specific MCA production. We characterized these mice with respect to BA metabolism and intestinal lipid absorption and delineated the (patho)physiological consequences of their hydrophobic BA composition. The hydrophobicity of the BA pool in Cyp2c70-deficient mice was comparable to that of the human BA pool. Cyp2c70-deficient mice were protected from diet-induced hepatic steatosis, which could be attributed to a reduction of intestinal fat absorption, pointing to a crucial role of 12α-hydroxylated BAs in fat absorption. The hydrophobic BA pool impacted the liver in Cyp2c70-deficient mice as cholangiopathic features were observed. Subsequently, the effects of selected pharmacological interventions were explored in this model. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) represent FDA-approved treatments for primary biliary cholangitis, while fisetin is a natural senolytic that has shown beneficial effects in a mouse model of cholangiopathy. Our data showed that UDCA treatment could restore the cholangiopathy, while OCA and fisetin treatment had only limited beneficial effects in Cyp2c70-deficient mice. The human-like BA profile and the presence of cholangiopathy make Cyp2c70-deficienct mice a useful model to investigate potential therapeutic approaches for cholangiopathies.

Dissertation: http://hdl.handle.net/11370/8261da65-cc62-4d29-9aa7-fe1140d59f44